Currently, clinical assessment of chronic kidney disease (CKD) depends upon estimates of glomerular filtration (eGFR) and glomerular injury (albuminuria). This two-dimensional assessment of glomerular health forms the backbone of recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines because each represents a different component of CKD and each provides prognostic information on adverse kidney and non-kidney outcomes independent of the other. As defined, CKD is an enormous public health problem, due to its high prevalence, its economic costs, and its adverse impact on morbidity and mortality. Beyond glomerular filtration and glomerular injury, the kidney has many other critical biological functions that are primarily mediated by the tubulointerstitium; these include proximal tubule reabsorption, electrolyte transport, acid/base homeostasis, and endocrine actions. Neither eGFR nor albuminuria captures tubulo- interstitial abnormalities. Our preliminary data strongly suggest that a comprehensive assessment of kidney health in adults will require the addition of measures of tubulo-interstitial injury and tubular function. The broa objective of this proposal will be to develop a Kidney Tubule Health Panel (KTHP) that will be comprised of established and novel measures of kidney tubule injury and dysfunction. For kidney tubule injury, we will evaluate and compare the prognostic value of urinary measures of proximal tubule injury, distal tubule injury, and interstitial fibrosis. For kidney tubule dysfuncton, we will evaluate the prognostic utility of endocrine resistance, metabolic acidosis, decreased proximal tubule reabsorption, and host defense. Outcomes of interest will include development of end-stage renal disease (ESRD), progressive loss of kidney function and development of hospitalized acute kidney injury (AKI) (Aims 1 and 2). In Aim 3 we will develop the KTHP utilizing novel statistical approaches to select a parsimonious set of biomarkers that will maximize the prediction of ESRD, progressive loss of kidney function, and AKI. We will address our hypotheses in the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) and the Multi-Ethnic Study of Atherosclerosis (MESA), as they offer a broad age range of participants, a large representation of whites, blacks, Asians, and Hispanics, detailed measures of kidney risk factors, available urine and serum specimens and the outcomes of ESRD, loss of kidney function and AKI over 10 years. By broadening the assessment of kidney health and disease beyond the glomerulus, we believe that our KTHP can ultimately lead to improved understanding, classification, prevention, and treatment of CKD. Our proposal includes a collaborative team of PIs, each with expertise in different components of the application, a long-standing history of collaboration, and extensive expertise in both cohorts.